The present invention relates to potentially pharmaceutical compositions and in particular to new molecules as active ingredients, that are used in particular as anticancer agents. Compounds of the general formula (I), or pharmaceutically acceptable salts thereof according to the present invention have an ability of inhibiting histone deacetylating enzyme and of inducing differentiation and are useful as therapeutic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections etc.
The novel stilbene like compounds (I) of the present invention are useful for the treatment cancer, which is one of the leading causes of death in the present society. A great deal of effort has been underway to treat various forms of cancer for decades and until recently. Chemoprevention of cancer is receiving its due share of attention.
Cancer may affect people at all ages, but risk tends to increase with age, due to the fact that DNA damage becomes more apparent in aging DNA. It is one of the principal causes of death in developed countries, more than 11 million people are diagnosed with cancer every year, and it is estimated that there will be 16 million new cases every year by 2020. Cancer causes 7 million deaths every year or 12.5% of deaths worldwide. Cancer is a leading cause of death worldwide particularly affecting major portion of people in industrialized world than in the non-industrialized world. From a total of 58 million deaths worldwide in 2005, cancer accounts for 7.6 million (or 13%) of all deaths. The main types of cancer leading to overall cancer mortality are Lung (1.3 million deaths/year), Stomach (almost 1 million deaths/year), Liver (662,000 deaths/year), Colon (655,000 deaths/year) and Breast (502,000 deaths/year). Deaths from cancer in the world are projected to continue rising, with an estimated 9 million people dying from cancer in 2015 and 11.4 million dying in 2030 (Parkin D et al, 2002)
Every cell constantly faces decisions. Should it divide? Or should it differentiate? Or should it die (Apoptosis)? Proper development and tissue homeostasis rely on the correct balance between division and apoptosis. Too much apoptosis leads to tissue atrophy such as in Alzheimer's disease. Too much proliferation or too little apoptosis leads to cancer. Cancer is a disease of multifactorial origin characterized by uncontrolled division of cells; when the cancer cell faces spatial restrictions, due to uncontrolled proliferation in an organ of the body, the ability of the cell to invade other distinct tissues occurs by a process defined as “Metastasis” the stage in which cancer cells are transported through the bloodstream or lymphatic system.
The most common treatment for easily accessible cancer is surgical removal of diseased tissues and radiation. The choice of treatment for in-accessible tumors is chemotherapy. Also chemotherapy is given as additional insurance for most cancer as it is difficult to access the extent of metastasis.
Most clinically revelant anticancer drugs currently used in the clinic, interfere with cell division and hence are not highly selective to cancer cells and there are potential chances, that chemotherapy can lead to secondary cancers in due course of time. Also the quality of life is hampered in the patients upon chemotherapy, hence there is an unmet medical need for treating cancer patients without affecting the quality of life. (Hill R P et al., 2005 & Kleinsmith, L J, 2006).
The cell cycle deregulation and the molecular basis of cancer cell growth has been thoroughly exploited in the recent years. Inhibition of signal transduction has become a viable and attractive avenue in biomedical cancer research based on the discovery of a large number of somatic mutations in many different types of cancer that lead to deregulated growth signal transduction and subsequent aberrant growth, invasion, tumor-derived angiogenesis and metastasis. Most of the noncytotoxic drugs that have been recently developed include Protein kinase inhibitors such as Gleevec, Iressa and Tarceva, Tyrosine kinase inhibitors like Leflunomide. Glivec™ (STI571), is an inhibitor of the bcr-abl kinase and CML. PKI166, on the other hand, is a dual inhibitor of EGF receptor (HER 1) as well as erbB (HER 2). EGF-receptor and PTK787, potent inhibitors of VEGF-receptor 2 (KDR) are able to suppress tumor growth via suppression of tumor angiogenesis and also these agents have entered clinical trials in tumor patients (Alex Matter, M.D., 2002). These types of orally active and relatively well-tolerated compounds can be used in the clinics; either as single agents or in combination with other well established cytotoxic agents.
Cytokines play an important role in the communication between cells of multicellular organisms. Early studies indicate that B cells lineage tend to secrete IL6 in response to host immune defense mechanisms, but in recent decades studies have indicated elevated levels of IL6 in various cancer phenotypes. IL6 promotes survival and proliferation of certain cancerous cell lines through the phosphorylation of STAT3 (Bharti et al., Verma et al., Kerr et al.). Inhibitors of Jak/Stat pathway likely represent potential therapeutic targets for cancer (Catlett Falcone et al., 1999; Alas and Bonavida, 2003; Burdelya et al., 2002)
IL6 has been found to be a growth factor for multiple myeloma cells; anti IL6 antibodies were shown to block myeloma cell proliferation in a leukemic patients (Lkein et al., Blood, 78, (5), pp 1198-1204, 1991 and Lu et al., Eur. J. Immunol., 22. 2819-24, 1992). A need exists for a compound that blocks IL6 mediated Stat3 activation at lower concentration and suppresses expression of proto-oncogenes like c-myc, which is over expressed, rearranged or mutated in many malignancies (Hallek et al., 1998; Selvanayagam et al., 1988; Jemberg-Wiklund et al., 1992; Kuehl et al., 1997).
Elevation of inflammatory cytokine levels, particularly IL-6 and TNF-α also appears to be associated with the Cancer-related cachexia, a syndrome involving loss of adipose and skeletal muscle tissue, and one that is not responsive to increased caloric intake. Cachexia may also be related to the role of acute phase proteins. The acute phase response and production of acute phase proteins (e.g., C-reactive protein CRP) are mediated by IL-6. Studies correlate elevated levels of IL-6 elevate acute phase proteins, which, interestingly, are also associated with increased weight loss and decreased survival. Thus, with elevated IL-6 levels, amino acid metabolism is directed away from peripheral tissues to the liver for production of acute phase proteins. This in turn leads to muscle wasting, which is a component of cachexia. Accordingly, the cytokine-induced acute phase response may be a primary component of cancer-related cachexia. Moreover, diminishing or blocking IL-6 activity in animal models attenuates cachexia, further demonstrating the essential role IL-6 plays in the development of this syndrome.
Resveratol, a representation of hydroxystilbene, is a plytoalexin present in grapes and other food products and has received special attention. It is known to possess a variety of biological significances such as cancer chemo-preventive activity, anti-inflammatory activity through inhibition of cyclooxygenase. It also inhibits arachidonate release, MAPK activation, protein kinase and degruanulation of mast cells and is a known antioxidant having anti-cancer as well as anti-diabetic activity. It has been suggested as a potential cancer chemo-preventive agent based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This triphenolic stilbene has also displayed in vitro growth inhibition in a number of human cancer cell lines.
Hypoglycemic activity of a naturally occurring pterostilbene, trans-1-(3,5-dimethoxyphenyl-2-(4-hydroxyphenyl)ethylene, and its isolation from the heartwood of pterocarpus marsupium have been reported by Manickam et al, J. Natu. Prod., 1997, 60:609-610.
NF-kB that plays an important role in INOS (inducible nitric oxide syntheses) expression is one of the targets of various potential anti-inflammatory agents including Resveratol.
The first isolation of histone deacetylase was described in 1964 from crude nuclear extracts of cells, but the molecular characterization of isoforms of the enzyme has been achieved only recently. Inhibitors of histone deacetylase (HDAC's) are zinc hydrolase's responsible for the deacetylation of N-acetyl lysine residues of histone and nonhistone protein substrates. Human HDAC's are classified into two distinct classes, the HDAC's and sirtuins. The HDAC's are devised into two subclasses based on their similarity to yeast histone deacetylases, RPD 3 (class I includes HDAC 1, 2, 3, 8, and 11) and Hda 1 (class II includes HDAC 4, 6, 7, 9, and 10). All of the HDAC's have a highly conserved zinc dependent catalytic domain. There is growing evidence that the acetylation state of proteins and thus the HDAC enzyme family plays a crucial role in the modulation of a number of biological processes, including transcription and cell cycle.
Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription factors to their target DNA regiments. Nucleosomal integrity is regulated by the acetylating status of the core histone, with the result being permissiveness to transcription. The acetylating status of the histone is governed by the balance of activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, t-cell lymphoma and erythroleukemic cells.
Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis.
Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P. A. et al., J. Natl. Cancer Inst., 92, (2000), 1210-1215. More specifically WO 98/55449 and U.S. Pat. No. 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity.
Few prior art references, which disclose the closest compounds, are given here:
I). U.S. Pat. No. 6,624,197 B1 discloses a class of novel diphenylethylenes of the formula I,
wherein R is hydrogen or —CO2Z, Z is hydrogen or a cation; and R1, R2 and R3 are each independently H, —OH or —OR4, wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the condition that when R is hydrogen and R2═R3=—OMe, then R1 is not —OH. The configuration around the double bond may be E/Z.A novel class of styrenes of the formula II is also provided,
wherein R5 is hydrogen or methyl; R6 and R7 are independently hydrogen or OMe; R8 is hydrogen or hydroxy. The configuration around the double bond may be E/Z. Pharmaceutical compositions of compounds of the formula I or II are provided for the treatment of diabetes comprising of therapeutically effective amount of the compounds in a physiologically acceptable carrier. A method of treating diabetes is also provided comprising a step of orally administering to a subject suffering from a diabetic condition a therapeutically effective amount of a compound of formula I or II.II). US 20050038125 discloses the invention related to a method for the treatment and/or prevention of disorders with elevated PGE2 (such as arthritis, fybromyalgia and pain) and/or LTB4 levels (such as asthma, allergy, arthritis, fybromyalgia and inflammation), comprising administering to a mammal an effective amount of pterostilbene component (PS component), a pharmaceutically acceptable salt of PS component or a precursor of PS component, wherein the PS component has the formula 1 as shown below
in which R1, R2 and R3 are independently selected from hydrogen, C1-50 hydrocarbyl, C1-50 so substituted hydrocarbyl, C1-50 heterohydrocarbyl, C1-50 substituted heterohydrocarbyl; and wherein at least one of R1 and R2 is not hydrogen